Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment

ABSTRACT

The present invention relates to carvedilol phosphate salts, which include novel crystalline forms of carvedilol dihydrogen phosphate (i.e., dihydrogen phosphate salt of 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol) and/or carvedilol hydrogen phosphate, etc.), and/or solvates thereof, compositions containing the aforementioned salts and/or solvates, and methods of using the aforementioned salts and/or solvates to treat hypertension, congestive heart failure and angina, etc.

This application is a divisional application of U.S. application Ser.No. 10/518,654, now U.S. Pat. No. 7,268,156, Filed Dec. 16, 2004, whichis a 371 application of PCT/US03/20408, Filed: Jun. 27, 2003, whichderives priority to U.S. Prov. Appln. Ser. No. 60/392,175, nowabandoned, Filed Jun. 27, 2002.

FIELD OF THE INVENTION

The present invention relates to a salt of carvedilol and/orcorresponding solvates thereof, compositions containing such a salt ofcarvedilol and/or corresponding solvates thereof, and/or methods ofusing the aforementioned compound(s) in the treatment of certain diseasestates in mammals, in particular man.

The present invention further relates to carvedilol phosphate salts,which include novel crystalline forms of carvedilol dihydrogen phosphate(i.e., such as dihydrogen phosphate salt of1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol),carvedilol hydrogen phosphate, etc.), and/or other correspondingsolvates thereof, compositions containing such salts and/or solvates,and methods of using the aformentioned compounds to treat hypertension,congestive heart failure and angina, etc.

BACKGROUND OF THE INVENTION

The compound, 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]-amino]-2-propanol is known as Carvedilol. Carvedilol is depictedby the following chemical structure:

Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al.(i.e., assigned to Boehringer Mannheim, GmbH, Mannheim-Waldhof, Fed.Rep. of Germany), which was issued on Mar. 5, 1985.

Currently, carvedilol is synthesized as free base for incorporation inmedication that is available commercially. The aforementioned free baseform of Carvedilol is a racemic mixture of R(+) and S(−) enantiomers,where nonselective β-adrenoreceptor blocking activity is exhibited bythe S(−) enantiomer and α-adrenergic blocking activity is exhibited byboth R(+) and S(−) enantiomers. Those unique features or characteristicsassociated with such a racemic Carvedilol mixture contributes to twocomplementary pharmacologic actions: i.e., mixed venous and arterialvasodilation and non-cardioselective, beta-adrenergic blockade.

Carvedilol is used for treatment of hypertension, congestive heartfailure and angina. The currently commercially available carvedilolproduct is a conventional, tablet prescribed as a twice-a-day (BID)medication in the United States.

Carvedilol contains an α-hydroxyl secondary amine functional group,which has a pKa of 7.8. Carvedilol exhibits predictable solubilitybehaviour in neutral or alkaline media, i.e. above a pH of 9.0, thesolubility of carvedilol is relatively low (<1 μg/mL). The solubility ofcarvedilol increases with decreasing pH and reaches a plateau near pH=5,i.e. where saturation solubility is about 23 μg/mL at pH=7 and about 100μg/mL at pH=5 at room temperature. At lower pH values (i.e., at a pH of1 to 4 in various buffer systems), solubility of carvedilol is limitedby the solubility of its protonated form or its corresponding saltformed in-situ. The hydrochloride salt of carvedilol generated in situin acidic medium, which simulates gastric fluid, is less soluble in suchmedium.

In light of the foregoing, a salt, and/or novel crystalline form ofcarvedilol with greater aqueous solubility, chemical stability, etc.would offer many potential benefits for provision of medicinal productscontaining the drug carvedilol. Such benefits would include productswith the ability to achieve desired or prolonged drug levels in asystemic system by sustaining absorption along the gastro-intestinaltract of mammals (i.e., such as humans), particularly in regions ofneutral pH, where a drug, such as carvedilol, has minimal solubility.

Surprisingly, it has now been shown that a novel crystalline form ofcarvedilol phosphate salt (i.e., such as carvedilol dihydrogen phosphateand/or carvedilol hydrogen phosphate, etc.) can be isolated as a pure,crystalline solid, which exhibits much higher aqueous solubility thanthe corresponding free base or other prepared crystalline salts ofcarvedilol, such as the hydrochloride salt. This novel crystalline formalso has potential to improve the stability of carvedilol informulations due to the fact that the secondary amine functional groupattached to the carvedilol core structure, a moiety pivotal todegradation processes, is protonated as a salt.

In light of the above, a need exists to develop different carvedilolforms and/or different compositions, respectively, which have greateraqueous solubility, chemical stability, sustained or prolonged drug orabsorption levels (i.e., such as in neutral gastrointestinal tract pHregions, etc.).

There also exists a need to develop methods of treatment forhypertension, congestive heart failure or angina, etc. which comprisesadministration of the aforementioned carvedilol phosphate salts and/orsolvates thereof or corresponding pharmaceutical compositions, whichcontain such salts, and/or solvates.

The present invention is directed to overcoming these and other problemsencountered in the art.

SUMMARY OF THE INVENTION

The present invention relates to a salt of carvedilol and/orcorresponding solvates thereof, compositions containing such carvediloland/or corresponding solvates thereof, and/or methods of using theaforementioned compound(s) in the treatment of certain disease states inmammals, in particular man.

The present invention further relates to carvedilol phosphate salts,which include novel crystalline forms of carvedilol phosphate (i.e.,such as dihydrogen phosphate salt of1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol),carvedilol hydrogen phosphate, etc.), and/or other correspondingsolvates thereof.

The present invention relates to a pharmaceutical composition, whichcontains carvedilol phosphate salts and/or solvates thereof.

The present invention further relates to a method of treatinghypertension, congestive heart failure and angina, which comprisesadministering to a subject in need thereof an effective amount of acarvedilol phosphate salt (which include novel crystalline forms) and/orsolvates thereof or a pharmaceutical composition (i.e., which containssuch salts and/or solvates of carvedilol phosphate), etc.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an x-ray powder diffractogram for carvedilol dihydrogenphosphate hemihydrate (Form I).

FIG. 2 shows the thermal analysis results for carvedilol dihydrogenphosphate hemihydrate (Form I).

FIG. 3 is an FT-Raman spectrum for carvedilol dihydrogen phosphatehemihydrate (Form I).

FIG. 4 is an FT-Raman spectrum for carvedilol dihydrogen phosphatehemihydrate in the 4000-2000 cm⁻¹ region of the spectrum (Form I).

FIG. 5 is an FT-Raman spectrum for carvedilol dihydrogen phosphatehemihydrate in the 2000-400 cm⁻¹ region of the spectrum (Form I).

FIG. 6 is an FT-IR spectrum for carvedilol dihydrogen phosphatehemihydrate (Form I).

FIG. 7 is an FT-IR spectrum for carvedilol dihydrogen phosphatehemihydrate in the 4000-2000 cm⁻¹ region of the spectrum (Form I).

FIG. 8 is an FT-IR spectrum for carvedilol dihydrogen phosphatehemihydrate in the 2000-500 cm⁻¹ region of the spectrum (Form I).

FIG. 9 is an x-ray powder diffractogram for carvedilol dihydrogenphosphate dihydrate (Form II).

FIG. 10 shows the thermal analysis results for carvedilol dihydrogenphosphate dihydrate (Form II).

FIG. 11 is an FT-Raman spectrum for carvedilol dihydrogen phosphatedihydrate (Form II).

FIG. 12 is an FT-Raman spectrum for carvedilol dihydrogen phosphatedihydrate in the 4000-2000 cm⁻¹ region of the spectrum (Form II).

FIG. 13 is an FT-Raman spectrum for carvedilol dihydrogen phosphatedihydrate in the 2000-400 cm⁻¹ region of the spectrum (Form II).

FIG. 14 is an FT-IR spectrum for carvedilol dihydrogen phosphatedihydrate (Form II).

FIG. 15 is an FT-IR spectrum for carvedilol dihydrogen phosphatedihydrate in the 4000-2000 cm⁻¹ region of the spectrum (Form II).

FIG. 16 is an FT-IR spectrum for carvedilol dihydrogen phosphatedihydrate in the 2000-500 cm⁻¹ region of the spectrum (Form II).

FIG. 17 shows the thermal analysis results for carvedilol dihydrogenphosphate methanol solvate (Form III).

FIG. 18 is an FT-Raman spectrum for carvedilol dihydrogen phosphatemethanol solvate (Form III).

FIG. 19 is an FT-Raman spectrum for carvedilol dihydrogen phosphatemethanol solvate in the 4000-2000 cm⁻¹ region of the spectrum (FormIII).

FIG. 20 is an FT-Raman spectrum for carvedilol dihydrogen phosphatemethanol solvate in the 2000-400 cm⁻¹ region of the spectrum (Form III).

FIG. 21 is an FT-IR spectrum for carvedilol dihydrogen phosphatemethanol solvate (Form III).

FIG. 22 is an FT-IR spectrum for carvedilol dihydrogen phosphatemethanol solvate in the 4000-2000 cm⁻¹ region of the spectrum (FormIII).

FIG. 23 is an FT-IR spectrum for carvedilol dihydrogen phosphatemethanol solvate in the 2000-500 cm⁻¹ region of the spectrum (Form III).

FIG. 24 is an x-ray powder diffractogram for carvedilol dihydrogenphosphate methanol solvate (Form III).

FIG. 25 is an x-ray powder diffractogram for carvedilol dihydrogenphosphate dihydrate (Form IV).

FIG. 26 is a solid state ¹³C NMR for carvedilol dihydrogen phosphatedihydrate (Form I).

FIG. 27 is a solid state ³¹P NMR for carvedilol dihydrogen phosphatedihydrate (Form I).

FIG. 28 is an x-ray powder diffractogram for carvedilol dihydrogenphosphate (Form V).

FIG. 29 is an x-ray powder diffractogram for carvedilol hydrogenphosphate (Form VI).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a salt of carvedilol and/orcorresponding solvates thereof, compositions containing such carvedilolsalts and/or corresponding solvates thereof, and/or methods of using theaforementioned compound(s) in the treatment of certain disease states inmammals, in particular man.

The present invention further relates to carvedilol phosphate salts,which include novel crystalline forms of carvedilol dihydrogen phosphate(i.e., such as dihydrogen phosphate salt of1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol),carvedilol hydrogen phosphate, etc.) and/or other carvedilol phosphatesolvates thereof.

The present invention relates to a pharmaceutical composition, whichcontains carvedilol phosphate salts and/or solvates thereof.

The present invention further relates to a method of treatinghypertension, congestive heart failure and angina, which comprisesadministering to a subject in need thereof an effective amount of acarvedilol phosphate salt (which include novel crystalline forms),and/or solvates thereof or a pharmaceutical composition (i.e., whichcontains such salts and/or solvates of carvedilol phosphate), etc.

Carvedilol is disclosed and claimed in U.S. Pat. No. 4,503,067 toWiedemann et al. (“U.S. '067 Patent”). Reference should be made to U.S.'067 Patent for its full disclosure, which include methods of preparingand/or using the carvedilol compound, etc. The entire disclosure of theU.S. '067 Patent is incorporated hereby by reference in its entirety.

The present invention relates to a compound, which is a salt and/ornovel crystalline forms of carvedilol phosphate (i.e., which includecrystalline forms of carvedilol dihydrogen phosphate, carvedilolhydrogen phosphate, etc.) and/or solvates of carvedilol phosphate (i.e.,which include carvedilol dihydrogen phosphate hemihydrate, carvediloldihydrogen phosphate dihydrate (i.e., such as Forms II and IV,respectively, etc.), and/or carvedilol dihydrogen phosphate methanolsolvate, etc.)

In accordance with the present invention, it has been unexpectedly foundthat carvedilol dihydrogen phosphate can be isolated readily as novelcrystalline forms, which displays much higher solubility when comparedto the free base of carvedilol. An example in the present invention of anovel carvedilol phosphate salt is a novel crystalline form ofcarvedilol dihydrogen phosphate (i.e., identified as the dihydrogenphosphate salt of 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol).

In accordance with the present invention, other carvedilol phosphatesalts, and/or solvates of the present invention may be isolated asdifferent solid and/or crystalline forms. Moreover, a specificidentified species of a carvedilol phosphate salt (or a specificidentified corresponding solvate species) also may also be isolated invarious different crystalline or solid forms. For example, carvediloldihydrogen phosphate, may be isolated in two different and distinctcrystalline forms, Forms II and IV (see, Examples 2 and 4), respectivelyrepresented and substantially shown FIGS. 9 to 6 (for Form II) and FIG.25 (for Form IV), which are represent spectroscopic and/or othercharacterizing data.

It is recognized that the compounds of the present invention may existin forms as stereoisomers, regioisomers, or diastereiomers, etc. Thesecompounds may contain one or more asymmetric carbon atoms and may existin racemic and optically active forms. For example, carvedilol may existas as racemic mixture of R(+) and S(−) enantiomers, or in separaterespectively optically forms, i.e., existing separately as either theR(+) enantiomer form or in the S(+) enantiomer form. All of theseindividual compounds, isomers, and mixtures thereof are included withinthe scope of the present invention.

Suitable solvates of carvedilol phosphate as defined in the presentinvention, include, but are not limited to carvedilol dihydrogenphosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate (i.e.,which include Forms II and IV, respectively), carvedilol dihydrogenphosphate methanol solvate, and carvedilol hydrogen phosphate, etc.

In particular, crystalline carvedilol dihydrogen phosphate hemihydrateof the instant invention can be prepared by crystallization from anacetone-water solvent system containing carvedilol and H₃PO₄.

In accordance with the present invention suitable, solvates of thepresent invention may be prepared by preparing a slurrying a carvedilolphosphate salt, such as a carvedilol dihydrogen salt, in a solvent, suchas methanol.

According to the instant invention, the various forms of carvediloldihydrogen phosphate (i.e. which include salts and/or solvates thereof)are distinguished from each other using different characterization oridentification techniques. Such techniques, include solid state ¹³CNuclear Magnetic Resonance (NMR), ³¹P Nuclear Magnetic Resonance (NMR),Infrared (IR), Raman, X-ray powder diffraction, etc. and/or othertechniques, such as Differential Scanning Calorimetry (DSC) (i.e., whichmeasures the amount of energy (heat) absorbed or released by a sample asit is heated, cooled or held at constant temperature).

In general, the aforementioned solid state NMR techniques arenon-destructive techniques to yield spectra, which depict an NMR peakfor each magnetically non-equivalent carbon site the solid-state Forexample, in identification of compounds of the present invention, ¹³CNMR spectrum of a powdered microcrystalline organic molecules reflectthat the number of peaks observed for a given sample will depend on thenumber of chemically unique carbons per molecule and the number ofnon-equivalent molecules per unit cell. Peak positions (chemical shifts)of carbon atoms reflect the chemical environment of the carbon in muchthe same manner as in solution-state ¹³C NMR. Although peaks canoverlap, each peak is in principle assignable to a single type ofcarbon. Therefore, an approximate count of the number of carbon sitesobserved yields useful information about the crystalline phase of asmall organic molecule.

Based upon the foregoing, the same principles apply to phosphorus, whichhas additional advantages due to high sensitivity of the ³¹P nucleus.

Polymorphism also can be studied by comparison of ¹³C and ³¹P spectra.In the case of amorphous material, broadened peak shapes are usuallyobserved, reflecting the range of environments experienced by the ¹³C or³¹P sites in amorphous material types.

Specifically, carvedilol dihydrogen phosphate salts, hydrates, and/orsolvates thereof, substantially shown by the data described in FIGS.1-29.

For example, crystalline carvedilol dihydrogen phosphate hemihydrate(see, Example 1: Form I) is identified by an x-ray diffraction patternas shown substantially in FIG. 1, which depicts characteristic peaks indegrees two-theta (2θ): i.e., 7.0±0.2 (2θ), 11.4±0.2 (2θ), 15.9±0.2(2θ), 18.8±0.2 (2θ), 20.6±0.2 (2θ), 22.8±0.2 (2θ), and 25.4±0.2 (2θ).

Crystalline carvedilol dihydrogen phosphate dihydrate (see, Example 2:Form II) is identified by an x-ray diffraction pattern as shownsubstantially in FIG. 9, which depicts characteristic peaks in degreestwo-theta (2θ): i.e., 6.5±0.2 (2θ), 7.1±0.2 (2θ), 13.5±0.2 (2θ),14.0±0.2 (2θ), 17.8±0.2 (2θ), 18.9±0.2 (2θ), and 21.0±0.2 (2θ).

Crystalline carvedilol dihydrogen phosphate methanol solvate (see,Example 3: Form III) is identified by an x-ray diffraction pattern asshown substantially in FIG. 24, which depicts characteristic peaks indegrees two-theta (2θ): i.e., 6.9±0.2 (2θ), 7.2±0.2 (2θ), 13.5±0.2 (2θ),14.1±0.2 (2θ), 17.8±0.2 (2θ), and 34.0±0.2 (2θ).

Crystalline carvedilol dihydrogen phosphate dihydrate (see, Example 4:Form IV) is identified by an x-ray diffraction pattern as shownsubstantially in FIG. 25, which depicts characteristic peaks in degreestwo-theta (2θ): i.e., 6.4±0.2 (2θ), 9.6±0.2 (2θ), 16.0±0.2 (2θ),18.4±0.2 (2θ), 20.7±0.2 (2θ), and 24.5±0.2 (2θ).

Crystalline carvedilol dihydrogen phosphate (see, Example 5: Form V) isidentified by an x-ray diffraction pattern as shown substantially inFIG. 28, which depicts characteristic peaks in degrees two-theta (2θ):i.e., 13.2±0.2 (2θ), 15.8±0.2 (2θ), 16.3±0.2 (2θ), 21.2±0.2 (2θ),23.7±0.2 (2θ), and 26.0±0.2 (2θ).

Crystalline carvedilol hydrogen phosphate (see, Example 6: Form VI) isidentified by an x-ray diffraction pattern as shown substantially inFIG. 29, which depicts characteristic peaks in degrees two-theta (2θ):i.e., 5.5±0.2 (2θ), 12.3±0.2 (2θ), 15.3±0.2 (2θ), 19.5±0.2 (2θ),21.6±0.2 (2θ), and 24.9±0.2 (2θ).

The present invention also relates to a pharmaceutical composition,which contains a salt of carvedilol phosphate and/or correspondingsolvates thereof.

Importantly, the chemical and/or physical properties of carvedilol formsdescribed herein, which include salts of carvedilol dihydrogenphosphates, such as novel crystalline forms, and/or solvates thereofindicate that those forms may be particularly suitable for inclusion inmedicinal agents, pharmaceutical compositions, etc.

For example, solubility of various carvedilol salts, and/or solvates asthose described herein may facilitate provision or development of adosage form from which the drug substance becomes available forbioabsorption throughout the gastrointestinal tract (i.e., in particularthe lower small intestine and colon). In light of the foregoing, it maybe possible to develop stable controlled release dosage forms containingsuch carvedilol phosphate salts and/or solvates of the presentinvention, etc., for once-per-day dosage, delayed release or pulsatilerelease to optimize therapy by matching pharmacokinetic performance withpharmacodynamic requirements.

Compounds or compositions within the scope of this invention include allcompounds or compositions, wherein the compound of the present inventionis contained in an amount effective to achieve its intended purpose.While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.

Thus, this invention also relates to a pharmaceutical compositioncomprising an effective amount of carvedilol dihydrogen phosphate saltsand/or solvates thereof, with any of the characteristics noted herein,in association with one or more non-toxic pharmaceutically acceptablecarriers and/or diluents thereof, and if desired, other activeingredients.

Moreover, the quantity of the compound or composition of the presentinvention administered will vary depending on the patient and the modeof administration and can be any effective amount.

Treatment regimen for the administration of the compounds and/orcompositions of the present invention can also be determined readily bythose with ordinary skill in art. The quantity of the compound and/orcomposition of the present invention administered may vary over a widerange to provide in a unit dosage an effective amount based upon thebody weight of the patient per day to achieve the desired effect.

In particular, a composition of the present invention is presented as aunit dose and taken preferably from 1 to 2 times daily, most preferablyonce daily to achieve the desired effect.

Depending upon the treatment being effected, the compounds, and/or orcompositions of the present invention can be administered orally,intravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically. Preferably, the composition is adapted for oraladministration.

In general, pharmaceutical compositions of the present invention areprepared using conventional materials and techniques, such as mixing,blending and the like.

In accordance with the present invention, compounds and/orpharmaceutical composition can also include, but are not limited to,suitable adjuvants, carriers, excipients, or stabilizers, etc. and canbe in solid or liquid form such as, tablets, capsules, powders,solutions, suspensions, or emulsions, etc.

Typically, the composition will contain a compound of the presentinvention, such as a salt of carvedilol or active compound(s), togetherwith the adjuvants, carriers and/or excipients. In particular, apharmaceutical composition of the present invention comprises aneffective amount of a salt of carvedilol (i.e., such as carvediloldihydrogen phosphate salts) and/or corresponding solvates (i.e., asidentified herein) thereof, with any of the characteristics notedherein, in association with one or more non-toxic pharmaceuticallyacceptable carriers and/or diluents thereof, and if desired, otheractive ingredients.

In accordance with the present invention, solid unit dosage forms can beconventional types known in the art. The solid form can be a capsule andthe like, such as an ordinary gelatin type containing the compounds ofthe present invention and a carrier, for example, lubricants and inertfillers such as, lactose, sucrose, or cornstarch, etc. In anotherembodiment, these compounds are tableted with conventional tablet basessuch as lactose, sucrose, or cornstarch in combination with binders likeacacia, cornstarch, or gelatin, disintegrating agents, such ascornstarch, potato starch, or alginic acid, and a lubricant, likestearic acid or magnesium stearate, etc.

The tablets, capsules, and the like can also contain a binder, such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin, etc. When thedosage unit form is a capsule, it can contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets can be coatedwith shellac, sugar, or both, etc. A syrup can contain, in addition toactive ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye, and flavoring such as cherry ororange flavor, etc.

For oral therapeutic administration, these active compounds can beincorporated with excipients and used in the form of tablets, capsules,elixirs, suspensions, syrups, and the like. The percentage of thecompound in compositions can, of course, be varied as the amount ofactive compound in such therapeutically useful compositions is such thata suitable dosage will be obtained.

Typically in accordance with the present invention, the oral maintenancedose is between about 25 mg and about 50 mg, preferably given oncedaily. In accordance with the present invention, the preferred unitdosage forms include tablets or capsules.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they can be enclosed in hard or soft shell capsules,or they can be compressed into tablets, or they can be incorporateddirectly with the food of the diet, etc.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form should be sterile and should befluid to the extent that easy syringability exists. It should be stableunder the conditions of manufacture and storage and should be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol, andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils, etc.

The compounds or pharmaceutical compositions of the present inventionmay also be administered in injectable dosages by solution or suspensionof these materials in a physiologically acceptable diluent with apharmaceutical adjuvant, carrier or excipients. Such adjuvants, carriersand/or excipients, include, but are not limited to sterile liquids, suchas water and oils, with or without the addition of a surfactant andother pharmaceutically and physiologically acceptable carrier, includingadjuvants, excipients or stabilizers, etc. Illustrative oils are thoseof petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, or mineral oil, etc. In general, water, saline,aqueous dextrose and related sugar solution, and glycols, such aspropylene glycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions, etc.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil, etc. In general, water, saline,aqueous dextrose and related sugar solution, and glycols such as,propylene glycol or polyethylene glycol, etc., are preferred liquidcarriers, particularly for injectable solutions. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The compounds and/or compositions prepared according to the presentinvention can be used to treat warm blooded animals, such as mammals,which include humans.

Conventional administration methods may be suitable for use in thepresent invention.

The present invention further relates to a method of treatinghypertension, congestive heart failure and angina, which comprisesadministering to a subject in need thereof an effective amount of acarvedilol phosphate salt (i.e., which include novel crystalline forms)and/or solvates thereof or a pharmaceutical composition (i.e., whichcontains such salts and/or solvates of carvedilol phosphate), etc.

The Examples set forth below are illustrative of the present inventionand are not intended to limit, in any way, the scope of the presentinvention.

EXAMPLES Example 1 Form I Carvedilol Dihydrogen Phosphate HemihydratePreparation

A suitable reactor is charged with acetone. The acetone solution issequentially charged with carvedilol and water. Upon addition of thewater, the slurry dissolves quicky. To the solution is added aqueousH₃PO₄. The reaction mixture is stirred at room temperature andcarvedilol dihydrogen phosphate seeds are added in one portion. Thesolid precipitate formed is stirred, then filtered and the collectedcake is washed with aqueous acetone. The cake is dried under vacuum to aconstant weight. The cake is weighed and stored in a polyethylenecontainer.

Example 2 Form II Carvedilol Dihydrogen Phosphate Dihydrate Preparation

Form I is slurried in acetone/water mixture between 10 and 30° C. forseveral days.

Example 3 Form III Carvedilol Dihydrogen phosphate Methanol SolvatePreparation

Form I is slurried in methanol between 10 and 30° C. for several days.

Example 4 Form IV—Carvedilol Dihydrogen Phosphate Dihydrate Preparation

Carvedilol dihydrogen dihydrogen phosphate is dissolved in anacetone/water mixture. The acetone is removed by distillation. A solidcrystallizes during acetone removal and is filtered and dried.

Example 5 Form V—Carvedilol Dihydrogen Phosphate Preparation

Carvedilol dihydrogen phosphate hemihydrate (Form I) was suspended inwater, and the suspension was placed on a mechanical shaker at roomtemperature. After 48 hours of shaking, the solid was isolated fromsuspension by filtration, then dried in a desiccator under vacuum for afew days.

Example 6 Form VI—Carvedilol Hydrogen Phosphate Preparation

A suitable reactor is charged with acetone. The acetone solution issequentially charged with SK&F 105517 and water. Upon addition of thewater, the slurry dissolves quicky. To the solution is added aqueousH3PO4 (at ½ the molar quantity of Carvedilol). The reaction mixture isstirred and allowed to crystallize. The solid precipitate formed isstirred and cooled, then filtered and the collected cake is washed withaqueous acetone.

Example 7 ¹³C and ³¹P Solid State NMR Data Analysis of CarvedilolDihydrogen Phosphate Hemihydrate (Form I)

A sample of carvedilol dihydrogen phosphate hemihydrate (Form I) wasanalyzed by solid-state ¹³C NMR and ³¹P NMR (i.e., to probe solidcompound form structure).

Carvedilol dihydrogen phosphate (Parent MW=406.5; Salt MW=504.5) has thefollowing structure and numbering scheme:

Experimental Details and ¹³C and ³¹P Analysis

The solid state ¹³C NMR methods used to analyze compounds of the presentinvention produce a qualitative picture of the types of carbon siteswithin the solid material. Because of variable polarization transferrates and the need for sideband suppression, the peak intensities arenot quantitative (much like the case in solution-state ¹³C NMR).

However, the ³¹P spectra are inherently quantitative.

For the ¹³C analysis, approximately 100 mg of sample was packed into a7-mm O.D. magic-angle spinning rotor and spun at 5 kHz. The ¹³C spectrumof the sample was recorded using a CP-TOSS pulse sequence(cross-polarization with total suppression of sidebands). An editedspectrum containing only quaternary and methyl carbons was then obtainedusing an CP-TOSS sequence with NQS (non-quaternary suppression). The ¹³Cspectra are referenced externally to tetramethylsilane via a sample ofsolid hexamethylbenzene.

For ³¹P Solid State NMR, approximately 40 mg of sample was packed into a4-mm O.D. rotor and spun at 10 kHz. Both CP-MAS and single-pulse MAS ³¹Ppulse sequences were used with ¹H decoupling. The ³¹P data areexternally referenced to 85% phosphoric acid by a secondary solid-statereference (triphenylphosphine oxide). The Bruker AMX2-360 spectrometerused for this work operates at ¹³C, ³¹P and ¹H frequencies of 90.556,145.782 and 360.097 MHz, respectively. All spectra were obtained at 298K.

Results and Discussion

The highly sensitive ¹³C and ³¹P Solid State NMR identification methodswere used for the analysis and characterization of a polymorphic form ofCarvedilol phosphate, which confirms its chemical structure in thesolid-state.

The form of Carvedilol dihydrogen phosphate is defined by these spectra,where both ¹³C and ³¹P spectra show clear and distinct differences.

In particular, FIG. 26 shows the ¹³C CP-TOSS spectrum of carevediloldihydrogen phosphate. An assignment of the numerous ¹³C resonances inFIG. 1 can be made by chemical shift assignment, the NQS spectrum andcomparisons with solution-state ¹³C assignments. At least twonon-equivalent molecules per unit cell are observed in this form ofCarvedilol phosphate.

FIG. 27 shows the ³¹P MAS spectrum of carvedilol dihydrogen phosphate. Asingle phosphorus signal is observed at 4.7 ppm, which is characteristicof phosphate salts.

It is to be understood that the invention is not limited to theembodiments illustrated hereinabove and the right is reserved to theillustrated embodiments and all modifications coming within the scope ofthe following claims.

The various references to journals, patents, and other publicationswhich are cited herein comprise the state of the art and areincorporated herein by reference as though fully set forth.

1. A compound which is carvedilol dihydrogen phosphate dihydrate havingan x-ray diffraction pattern which comprises characteristic peaks indegrees two-theta (2θ) as shown in FIG.
 9. 2. A compound which iscarvedilol dihydrogen phosphate dihydrate having characteristic peaksfrom 0° degrees 2-theta (2θ) to 35° degrees 2-theta (2θ) at about6.5±0.2 (2θ), 7.1±0.2 (2θ), 13.5 ±0.2 (2θ), 14.0±0.2 (2θ), 17.8±0.2(2θ), 18.9±0.2 (2θ), and 21.0±0.2 (2θ).
 3. A compound which iscarvedilol dihydrogen phosphate dihydrate having an x-ray diffractionpattern which comprises characteristic peaks in degrees two-theta (2θ)as shown in FIG.
 25. 4. A compound which is carvedilol dihydrogenphosphate dihydrate having characteristic peaks from 0° degrees 2-theta(2θ) to 35° degrees 2-theta (2θ) at about 6.4±0.2 (2θ), 9.6±0.2 (2θ),16.0 ±0.2 (2θ), 18.4±0.2 (2θ), 20.7±0.2 (2θ), and 24.5±0.2 (2θ).